SUMMARY A major gap in the ?bench to bedside? paradigm is the ability to harness the glycome for the development of novel therapeutics. Although decades of research in glycobiology have established glycomic changes associated with disease, almost nothing is known about how those changes arise, the functions they play in disease initiation or progression, or how the glycome is actually regulated. Based on provocative new data, we propose a transformative new model for glycomic compositional regulation that provides a clear path for the development of the first generation of glycan-modulating therapies for a wide range of diseases. We call this ?exogenous glycosylation? based on the extracellular nature of the glycan modifications, and if correct, our findings will refute the glycobiology dogma in which glycomic changes are dependent upon the slow process of protein turnover and de novo synthesis to one that is highly dynamic, rapid, and specific to the environment. The proposal centers on the cellular and molecular action of ST6Gal1, the transferase responsible for adding ?2,6- linked sialic acids onto glycoproteins. More specifically, this enzyme is the sole molecule that determines whether anti-inflammatory ?2,6-sialyl-IgG or asialyl-IgG is produced at any given time, thereby making it a key immunomodulatory factor. In Aim 1, we will dissect the biochemistry and enzymatic action of ST6Gal1 in B cells during IgG production. In Aim 2, we will extend our efforts to the liver, which is a major in vivo source of the enzyme. Even if the `exogenous glycosylation' pathway is limited to sialylation, such a pathway could influence immune pathways such as leukocyte trafficking, the distinction between self and non-self by siglecs, synthesis of the ABO blood groups, transplantation, IgG functionality and many others 9. Our findings could redefine the nature of the glycome as one under dynamic regulation that could be therapeutically harnessed via the creation of an entirely new class of glycosylation-altering drugs for the treatment of diseases ranging from inflammatory disorders and autoimmunity to cancer.